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Early neonatal vitamin A supplementation and infant mortality: an individual participant data meta-analysis of randomised controlled trials
  1. Neonatal Vitamin A Supplementation Evidence group
    1. Correspondence to Dr Rajiv Bahl, Department of Maternal, Newborn, Child and Adolescent Health, World Health Organization, Geneva 27, Switzerland; bahlr{at}who.int

    Abstract

    Background Biannual vitamin A supplementation is a well-established survival tool for preschool children 6 months and older in vitamin A deficient populations but this schedule misses the opportunity to intervene on most young infant deaths. Randomised trials of neonatal vitamin A supplementation (NVAS) in the first few days of life to assess its impact on under 6-month mortality in low/middle-income countries have had varying results.

    Methods Investigators of 11 published randomised placebo-controlled NVAS trials (n=163 567 children) reanalysed their data according to an agreed plan and pooled the primary outcomes of mortality from supplementation through 6 and 12 months of age using random effects models and meta-regression. One investigator withdrew but allowed use of the data.

    Findings Overall there was no effect of NVAS on infant survival through 6 (risk ratio (RR) 0.97; 95% CI 0.89 to 1.06) or 12 months of age (RR 1.00; 95% CI 0.93 to 1.08) but results varied by study population characteristics.

    NVAS significantly reduced 6-month mortality among the trials conducted in Southern Asia (RR 0.87; 95% CI 0.77 to 0.98), in contexts with moderate or severe vitamin A deficiency (defined as 10% or higher proportion of women with serum retinol <0.7 µmol/L or 5% or more women with night blindness) (RR 0.87; 95% CI 0.80 to 0.94), early infant mortality was 30 or more per 1000 live births (RR 0.91; 95% CI 0.85 to 0.98), 75% or more of infant mortality occurred in the first 6 months of life (RR 0.92; 95% CI 0.84 to 1.01), or where >32% mothers had no schooling (RR 0.88; 95% CI 0.80 to 0.96). NVAS did not reduce mortality in the first 6 months of life in trials conducted in Africa, in contexts characterised by a low prevalence of vitamin A deficiency, lower rates of infant mortality and where maternal education was more prevalent. There was a suggestion of increased infant mortality in trials conducted in Africa (RR 1.07; 95% CI 1.00 to 1.15).

    Individual-level characteristics such as sex, birth weight, gestational age and size, age at dosing, parity, time of breast feeding initiation, maternal education and maternal vitamin A supplementation did not modify the impact of NVAS.

    Conclusion NVAS reduced infant mortality in South Asia, in contexts where the prevalence of maternal vitamin A deficiency is moderate to severe and early infant mortality is high; but it had no beneficial effect on infant survival in Africa, in contexts where the prevalence of maternal vitamin A deficiency is lower, early infant mortality is low.

    • infant mortality
    • neonatal vitamin A supplementation

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    Footnotes

    • Author group Neonatal Vitamin A Supplementation Evidence Group

    • Bangladesh: Keith P West,1 Lee S-F Wu,1 Hasmot Ali,2 Rolf D W Klemm1,3

      Ghana: Karen Edmond,4 Lisa Hurt,5 Betty Kirkwood,6 Sam Newton,7 Caitlin Shannon8

      India-Haryana: Sunita Taneja,9 Sarmila Mazumder,9 Kiran Bhatia,9 Nita Bhandari,9

      India-Tamil Nadu: Joanne Katz10 and James M Tielsch11

      Indonesia: Jean Humphrey,12 Lee S-F Wu,1 Tina Agoestina13

      Pakistan: Sajid Soofi,14 Shabina Ariff,14 Zaid Bhatti,14 Simon Cousens,6 Zulfiqar A Bhutta15

      Zimbabwe: Jean Humphrey12 and Robert Ntozini16

      Tanzania: Honorati Masanja,17 Emily R Smith,18 Alfa Muhihi,19 Wafaie Fawzi18

      Coordination (WHO): Rajiv Bahl,20 Jose Martines,21 Sachiyo Yoshida20

    • Author affiliations 1 Center for Human Nutrition, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA

      2 The JiVitA Project, Johns Hopkins University Bangladesh, Baibandha, Bangladesh

      3 Helen Keller International, New York City, New York, USA

      4 University of Western Australia, Perth, Western Australia, Australia

      5 Cardiff University, Cardiff, UK

      6 London School of Hygiene and Tropical Medicine, London, UK

      7 Kwame Nkrumah University of Science and Technology, Kumasi, Ghana

      8 Engender Health, New York City, New York, USA

      9 Centre for Health Research and Development, New Delhi, Delhi, India

      10 Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA

      11 Milken Institute School of Public Health, George Washington University, Washington, DC, USA

      12 Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA

      13 Hasan Sadikin Hospital, Bandung, Indonesia

      14 Department of Pediatrics and Child Health, The Aga Khan University, Karachi, Sindh, Pakistan

      15 Centre of Excellence in Women and Child Health, The Aga Khan University, Aga Khan, Karachi, Pakistan

      16 Zvitambo Institute for Maternal and Child Health Research, Harare, Zimbabwe

      17 Ifakara Health Institute, Dar es Salaam, Tanzania

      18 Harvard TH Chan School of Public Health, Boston, Massachusetts, USA

      19 Africa Academy for Public Health, Dar es Salaam, Tanzania

      20 Department of Maternal, Newborn, Child and Adolescent Health, World Health Organization, Geneva, Switzerland

      21 CISMAC, Centre for International Health, University of Bergen, Bergen, Norway

    • Contributors KPW, LSFW, RDWK, KME, LH, BK, SN, CS, ST, SM, KB, NB, JK, JMT, JH, SBS, SA, RN, HM, ERS, AM, WF, RB, JM and SY participated in the workshop to develop a harmonised pooled analysis protocol and contributed to development of the meta-analysis plan. KH, CS, LSFW, KB, JK, ZAB, SC, RN, ERS and AM analysed the site-specific data. RB, JM and SY consolidated the database and conducted the meta-analysis. ERS wrote the first draft of the manuscript. All authors reviewed, provided the comments and approved the final manuscript.

    • Funding The meeting of study investigators was organised by the WHO, with financial support from the Bill and Melinda Gates Foundation.

    • Competing interests JMT received grants from USAID, other from Task Force Sight & Life, during the conduct of the study. JK received grants from Bill and Melinda Gates Foundation, USAID, and Task Force Sight and Life, during the conduct of the original study contributing to this pooled analysis. KPW received within the past 3 years an award from the Sight and Life Foundation and DSM to support scholarships and academic activities within the programme in Human Nutrition. DSM has prepared gratis nutrient supplement for research.

    • Patient consent Not required.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Collaborators Neonatal Vitamin A Supplementation Evidence Group Bangladesh: Keith P West,1 Lee S-F Wu,1 Hasmot Ali,2 Rolf D W Klemm1,3 Ghana: Karen Edmond,4 Lisa Hurt,5 Betty Kirkwood,6 Sam Newton,7 Caitlin Shannon8 India-Haryana: Sunita Taneja,9 Sarmila Mazumder,9 Kiran Bhatia,9 Nita Bhandari,9 India-Tamil Nadu: Joanne Katz10 and James M Tielsch11 Indonesia: Jean Humphrey,12 Lee S-F Wu,1 Tina Agoestina13 Pakistan: Sajid Soofi,14 Shabina Ariff,14 Zaid Bhatti,14 Simon Cousens,6 Zulfiqar A Bhutta15 Zimbabwe: Jean Humphrey12 and Robert Ntozini16 Tanzania: Honorati Masanja,17 Emily R Smith,18 Alfa Muhihi,19 Wafaie Fawzi18 Coordination (WHO): Rajiv Bahl,20 Jose Martines,21 Sachiyo Yoshida20

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